tbuckley/cabot-search huggingface dataset:
EPID-06. Transfusion related iron overload in pediatric patients with CNS tumors
Authors: Shelby Winzent-Oonk, Amanda Winters, Aneisia Pounds, Holly Pacenta, Jean Mulcahy Levy, Christopher McKinney
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Patients receiving chemotherapy or autologous hematopoietic stem cell transplant (autoHSCT) routinely receive red cell transfusions as supportive care. Each unit of transfused red cells contains approximately 150mg of iron which the body has no natural mechanism for excreting. Transfusion-related iron overload (TRIO) is an under-recognized complication of therapy which left untreated may result in long-term damage to the liver, heart, or endocrine organs. We sought to identify the prevalence of TRIO in patients with pediatric CNS tumors and evaluate specific risk factors. METHODS: A retrospective record review of pediatric CNS tumor patients treated at Children’s Hospital Colorado was conducted including patients who completing therapy between 1/1/2014 – 12/1/2021. Patients at high risk for TRIO were defined as having a cumulative transfused blood volume of more than 150mL/kg or 4000mL total. The diagnosis of TRIO was confirmed if patients had a serum ferritin greater than 1000ng/mL or elevated liver iron content of 7mg/g dry weight or greater by MRI. RESULTS: There were 173 evaluable patients (40% embryonal tumors, 15% germ cell tumors, 10% ependymomas, 26% low grade gliomas, 5% high grade gliomas, and 3% other tumors). The mean age at completion of therapy was 8 years (range: 0.67 – 25 years). Patients receiving autoHSCT (24% of cohort) were at higher risk for TRIO based on transfused volumes (p&amp;lt;0.0001) than patients not treated with autoHSCT (72% vs 6%, RR 12.0) The prevalence of TRIO in autoHSCT patients was 7.5% (3/40) vs 0.8% (1/121) in patients not undergoing autoHSCT (RR 9.37). For autoHSCT patients at high risk by transfused volume the prevalence of TRIO was 10.3% (3/29). CONCLUSIONS: Pediatric CNS tumor patients who have received an autoHSCT are at higher risk for TRIO than those who have not. Routine screening for TRIO should be offered to patients receiving autoHSCT.
Characterization of the tumor immune microenvironment between primary and paired asynchronous metastatic clear cell renal cell carcinoma
Authors: B.H. Cotta, S. Nallandhighal, R. Mehra, M. Cieslik, M.W. Farha, A. Kasputis, T.M. Morgan, S.S. Salami
Journal: European Urology (2022)
Crizotinib in <i>ROS1</i>-rearranged lung cancer (EUCROSS): Updated overall survival.
Authors: Sebastian Yves Friedrich Michels, Jeremy Franklin, Bartomeu Massuti, Martin Sebastian, Enriqueta Felip, Christian Grohé, Delvys Rodriguez-Abreu, Helge Bischoff, Enric Carcereny, Jesús Corral, Amelia Insa, Martin Reck, Sacha Rothschild, Mariano Provencio, Matthias Scheffler, Martin Hellmich, Lucia Nogova, Reinhard Büttner, Rafael Rosell, Juergen Wolf
Journal: Journal of Clinical Oncology (2022)

9078 Background: ROS1 rearrangements are found in approximately 1% of non-small cell lung cancer (NSCLC) patients. Prospective clinical trials showed high efficacy of crizotinib in this molecular subset. Lately, we reported an overall response rate (ORR) of 70% and a median progression-free survival (PFS) of 19.4 months for patients treated within the EUCROSS trial (Michels et al. Clin Oncol, 37(15_suppl):9066-9066, 2019). Here we present an updated analysis of the overall survival. Methods: EUCROSS is a European multi-centre, single arm phase 2 trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria were ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation) and no or stable brain metastases at baseline. Crizotinib was given at a dose of 250 mg twice daily. Primary endpoint of the trial was investigator-assessed ORR in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1), with secondary endpoints of PFS and overall survival (OS). Results: Of the 34 patients who received at least one dose of crizotinib (intention-to-treat population, ITT), 30 were included the primary efficacy analysis set (PAS). After a median follow-up of 55.9 months, 13 (43%) patients in the PAS and 15 (44%) in the ITT had died. Median OS was not reached in either group (95% CI, 17.1-NR and 20.3-NR, respectively). OS was negatively correlated with the presence of brain metastases (Log-rank p = 0.1805) and TP53 mutations (Log-rank p = 0.015). Detailed listings of the survival rates are depicted in Table. No new safety signals were observed. Owing to the approval of crizotinib by the European Medicines Agency, all patients who were still on treatment by January 24 th 2018 (n=8), were prescribed crizotinib outside the trial. Conclusions: Updated OS highlights the efficacy of crizotinib in patients with ROS1-rearranged lung cancer. Patients with co-occurring TP53 mutations or brain metastases had worse outcomes and represent challenging populations. Clinical trial information: NCT02183870. [Table: see text]
Neoadjuvant pembrolizumab may result in long-term outcome improvement in biomarker-unselected patients with Muscle-Invasive Bladder Cancer (MIBC): Updated results from PURE-01
Authors: L. Nocera, M. Moschini, D. Raggi, L. Marandino, M. Colecchia, R. Lucianò, E.A. Gibb, J.S. Ross, A. Messina, G. Calareso, A. Gallina, F. Dehò, A. Briganti, F. Montorsi, A. Necchi
Journal: European Urology (2022)
Evaluation of uroLogical tEAching in bRitish medical school Nationally: the LEARN multicentre cross-sectional study
Authors: A. Asif, A. Ng, V.W-S. Chan, A. Light, C.M. Lam, K. Jayaraajan, W. Cambridge, M.G. Matthews, M. Kulkarni, N.R. Bhatt, S. Khadhouri, V. Kasivisvanathan
Journal: European Urology (2022)
IMMU-07. Interim analysis of the HIT-HGG Rez Immunvac study - Dendritic cell vaccination with partial Treg depletion and double checkpoint blockade in children with relapsed high-grade gliomas.
Authors: Matthias Eyrich, Jürgen Krauss, Maryam Ghaffari, Ignazio Caruana, Johannes Rachor, Camelia-Maria Monoranu, Brigitte Bison, Stefan Rückriegel, Matthias Wölfl, Elisabeth Miller, Paul-Gerhardt Schlegel, Christof Kramm
Journal: Neuro-Oncology (2022)

Abstract Relapses of high-grade gliomas show an aggressive course and survival 6 months after (sub-)total re-resection was only 62% in former HIT-HGG trials. Immunotherapy by induction of tumor-specific T cells through active immunization might help to control glioma regrowth. In the HIT-HGG-Rez Immunovac trial (Eudra-CT 2013-000419-26) we investigate whether a therapeutic vaccine (autologous dendritic cells loaded with tumor lysate, DCV) combined with Treg-depletion and double checkpoint-inhibition (CI, anti-PD-1/anti-CTLA4) is able to increase the number of patients alive 6 months after relapse. Here, we report interim results after 50% of the intended patients (n=25) have been recruited. 13 children and adolescents (mean age 12.7±4.0 y) with relapsed glioblastomas were screened for the trial so far. Three patients were screening failures, 10 patients received study treatment. Of these, 2 patients are currently vaccinated, so that 8 patients were evaluable for this interim analysis. 5 SAEs have been reported so far, none of them was limiting. 4 patients with gross total or subtotal resection at time of relapse had an overall survival (OS) of 13.2±4.0 months and a 6-month survival rate of 100%, which compares favourably to historical controls. 4 partially resected patients survived only 5.1±1.3 months and 6-months OS was 25%. Treg-depletion lead to a reduction of CD4+CD127-CD25+ T-cells of 45%, the majority of patients exhibited a tumor-specific T-cell response. We conclude that DCV in combination with partial Treg-depletion and CI is feasible, safe, and related with immunological responses. Double CI was not associated with unexpected toxicities. In (sub-)totally resected patients, immunotherapy seems to confer a survival advantage. For the completion of the trial we aim to include more patients with (sub-)totally resectable tumors to gain more insight into the nature and duration of the induced immune response. This trial is supported by Bristol Myers-Squibb (CA209-7JA).
Clinical pharmacokinetic/pharmacodynamic relationship of DZD2269, a potent and selective A2aR antagonist designed to overcome high levels of adenosine induced immunosuppression.
Authors: Ziyi Liu, Yu Bai, Dongdong Hu, Lin Zhang, Tanyada Yong, Zhenfan Yang
Journal: Journal of Clinical Oncology (2022)

e15106 Background: Extracellular adenosine suppresses immune cells’ function through binding to its receptor A2aR. In the tumor microenvironment, adenosine concentration could be several hundred-fold higher than in blood. DZD2269 was designed to fully block A2aR in a wide range of adenosine concentrations. In preclinical studies, DZD2269 could most effectively restore immune cell function inhibited by high levels of adenosine among A2aR antagonists currently in clinical studies. In mouse syngeneic prostate cancer model, DZD2269 could significantly enhance the antitumor activity of anti-PD1 antibody as well as radiotherapy. Two ongoing clinical studies of DZD2269 in healthy volunteers (PAN-GU 2, NCT04932005) and patients with metastatic castration resistant prostate cancer (PAN-GU 1, NCT04634344) are being conducted to characterize its safety, PK, PD and to assess its preliminary anti-tumor efficacy. Here, we report clinical data from the PAN-GU 2 study. Methods: The phase 1 healthy volunteer study is a double-blind, placebo-controlled study to evaluate safety, PK, and effect on biomarkers. It consists of three parts: single ascending dose (SAD): 5, 10, 20, 40, 80 and 160 mg; multiple ascending dose (MAD): from 10 mg BID for 7 consecutive days; and food effect (FE): fasted, low-fat or high-fat meal condition. A2aR pathway blockade by DZD2269 is evaluated by analyzing pCREB inhibition on whole blood T cells following ex vivo stimulation with 10 µM NECA. Results: In SAD part of the healthy volunteer study, a total of 48 subjects received a single oral dose of DZD2269 (n = 36) from 5 mg to 160 mg or placebo (n = 12). There were 7 TEAEs reported by 4 subjects and no ≥ grade 3 TEAE or SAE. After a single oral dose, the rate of absorption of DZD2269 was moderate (median t max : 1.0 to 2.75 hr). DZD2269 exhibited low to moderate clearance (averaged value: 16.1 to 45.3 L/h) and extensive volume of distribution (averaged value: 209 to 738 L), resulting in a mean t 1/2 of 7 ̃ 10 hr; a trend of increased t 1/2 was observed at higher dose levels. Systemic exposure of DZD2269 (AUC and C max ) increased in an approximately dose-dependent manner. Based on PK/PD analysis, approximately 90% pCREB inhibition could be achieved by a single dose of 80mg for 24 hours. Conclusions: Single oral dose of DZD2269 ranging from 5 mg to 160 mg was safe and well tolerated. Good PK/PD correlation was demonstrated in the study. DZD2269 could effectively reverse high adenosine induced immunosuppression. A phase1/2 study evaluating safety and efficacy of DZD2269 in patients is ongoing. Clinical trial information: NCT04932005.
CircVAPA promotes small cell lung cancer progression by modulating the miR-377-3p and miR-494-3p/IGF1R/AKT axis
Authors: Jinghan Hua, Xiaolin Wang, Liying Ma, Jingxin Li, Guozhen Cao, Shaobo Zhang, Wenchu Lin
Journal: Molecular Cancer (2022)

Multiple lines of evidence have demonstrated that circular RNAs (circRNAs) play oncogenic or tumor-suppressive roles in various human cancers. Nevertheless, the biological functions of circRNAs in small cell lung cancer (SCLC) are still elusive.CircVAPA (annotated as hsa_circ_0006990) was identified by mining the circRNA profiling dataset of six paired SCLC tissues and the RNA-seq data of serum samples from 36 SCLC patients and 118 healthy controls. The circVAPA expression level was evaluated using quantitative real-time PCR in SCLC cells and tissues. Cell viability, colony formation, cell cycle and apoptosis analysis assays and in vivo tumorigenesis were used to reveal the biological roles of circVAPA. The underlying mechanism of circVAPA was investigated by Western blot, RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay and rescue experiments.We revealed that circVAPA, derived from exons 2-4 of the vesicle-associated membrane protein-associated protein A (VAPA) gene, exhibited higher expression levels in SCLC cell lines, clinical tissues, and serum from SCLC patients than the controls, and facilitated SCLC progression in vitro and in vivo. Mechanistically, circVAPA activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by modulating the miR-377-3p and miR-494-3p/insulin-like growth factor 1 receptor (IGF1R) axis to accelerate SCLC progression. Furthermore, circVAPA depletion markedly enhanced the inhibitory effects of BMS-536924, an IGF1R kinase inhibitor in cellular and xenograft mouse models.CircVAPA promotes SCLC progression via the miR-377-3p and miR-494-3p/IGF1R/AKT axis. We hope to develop clinical protocols of combinations of circVAPA inhibition and BMS-536924 addition for treating SCLC with circVAPA upregulation.
<i>DACH1</i> mutation frequency in endometrial cancer is associated with high tumor mutation burden in a nationwide cohort.
Authors: McKayla J Riggs, Nan Lin, Rachel W. Miller, Dava West Piecoro, Bryan P. Schneider, Hye Sook Chon, John D. Carpten, Michelle L. Churchman, Bradley Corr, Christina Washington, Robert Dood, Stephen B. Edge, Aliza L. Leiser, Erin M. Siegel, Frederick West Ueland, Jill Kolesar
Journal: Journal of Clinical Oncology (2022)

e17634 Background: DACH1 is a novel transcriptional repressor and tumor suppressor gene. DACH1 mutations are associated with poor prognostic features and reduced overall survival in endometrial cancer, with an increased prevalence in the Appalachian region of Kentucky. Preliminary studies have suggested an association with an increase in tumor mutation burden. In this follow up study, we utilized the nationwide Oncology Research Information Exchange Network (ORIEN) to determine the frequency of DACH1 mutations in patients with endometrial cancer through a multi-institution analysis and evaluate its impact on RNA expression, clinical correlates, and outcomes. Methods: We obtained clinical and genomic data for 691 patients with endometrial cancer from nine U.S. institutions within the ORIEN collaborative. We examined the clinical attributes of the cancers with DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results: Appalachian women with endometrial cancer had an increased frequency of DACH1 mutations (6/41 patients, 15%) compared to the non-Appalachian endometrial cancer population (24/581 patients, 4.1%) with p-value = 0.010, with the non-Appalachian DACH1 mutation frequency mirroring the rate of DACH1 gene mutation seen in TCGA at 3.8%. DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (32.2 vs. 4.62, p-value = 0.001) though no differences in microsatellite instability between DACH1 mutated and wild-type were present (p-value = 0.350). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, MSH2, MSH6 and PMS2. Conclusions: DACH1 mutations are prevalent in Kentucky patients with endometrial cancer, particularly those from the Appalachian region. These results were again reflected in the TCGA PanCancer Atlas as well as the ORIEN multi-institution cohort. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 as a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.
Impact of an internal specialty pharmacy medication assistance program on the adherence rates of oral oncolytics.
Authors: Chaeok Jeon, Maya Leiva
Journal: Journal of Clinical Oncology (2022)

e18576 Background: High-cost medications pose a barrier to adherence which results in poor therapeutic outcomes and an increase in overall healthcare spending. Medication adherence is critical, especially in cancer patients, in order to achieve optimal, progression-free and disease-free survival. The projected cost of cancer continues to rise, putting patients at a greater risk for delayed treatment and nonadherence. This study evaluates the impact financial assistance has on medication adherence by comparing the oncolytic adherence rates found in published literature with the rates found in patients receiving financial assistance through an internal specialty pharmacy. Methods: This was a single-center, retrospective chart review evaluating patients over 18 years of age who received Hisaoka Cancer Fund and filled their oral oncolytic medications with the internal health system specialty pharmacy. The outpatient pharmacy software and electronic health records were utilized to run reports based on the eligibility criteria between January 1, 2020 and June 30, 2020. Patient demographics included age, gender, race, and cancer diagnosis. Patients younger than 18 years of age, who filled injectable oncolytics or supportive medications, have incomplete data, or were on off-label prescription drugs were excluded. The medication possession ratio (MPR) and time-to-treatment (TTT) in patients receiving the fund were compared to adherence rates found in the literature. Results: A total of 167 patients with a total of 297 prescription fills were evaluated. The MPRs had an average of 82.8% with a median of 92.8% (range 53.8% – 100%). The average TTT was 1.1 days, with a median of 0 day (range 0 – 12 days). In contrast, MPRs found in the two published studies were 75% and 61%, respectively and TTTs were found to be 10.9 and 27 days in those who filled medications through an external specialty pharmacy. A total of $12,793.43 was covered by the fund, with an average of $1,599.18 per patient during the six-month period. Conclusions: Adherence rates in patients who received the medication assistance program through internal health system specialty pharmacy exceeded the rates found in patients who filled medications from external pharmacies. The Hisaoka Fund reduced the financial burden by covering the cost of medications. Due to limited number of patients, further studies are needed to evaluate the impact of the medication assistance program on adherence rates across institutions.[Table: see text]
A potential mechanism of ferroptosis modulation for immunotherapy in LUAD: ceRNAs networks of OTUD6B-AS1 modulate the balance of ubiquitination.
Authors: Lintong Yao, HaiYu Zhou
Journal: Journal of Clinical Oncology (2022)

e15111 Background: Ferroptosis plays a pivotal role in cancer progression and therapeutic response of immunotherapy in lung adenocarcinoma (LUAD). Recent studies on ferroptosis regulation by lncRNAs were conducted sporadically. Our study explored FrlncRNAs in LUAD comprehensively, exploring functional mechanisms and verified the correlation between ferroptosis and ubiquitination. Methods: Data of LUAD samples were download from GEO and TCGA databases. Annotated ferroptosis-related genes were retrieved from FerrDb and GeneCards databases. Ferroptosis-related lncRNA (FrlncRNAs) was identified by correlation analysis. The LASSO analysis and cox regression analysis were performed to filtrate significant prognostic FrlncRNAs, followed with model construction and patient stratification. Tumor immune microenvironment, functional pathways were investigated. Subcellular location and potential competing endogenous RNAs (ceRNAs) mechanisms were predicted by GDCRNATools algorithm. Results: Ferroptosis-related prognostic model constructed by 14 FrlncRNAs signature showed high prognostic efficacy with significant survival difference and robust area under the curve (AUC for 5 years survival: 0.89 in training cohort and 0.87 in validation cohort). Higher proportion of myeloid-derived suppressor cells were detected in high-risk group, of which ferroptotic status were supressed. Ferroptosis-enhanced samples harboured higher expression of immune checkpoints such as PD-L1, CTLA-4, TIM3 and CD47 and immune-recruiting interleukins such as IL2, IL4, IL7. Reasonably, more potential responders to immunotherapy were predicted in ferroptosis-enhanced samples. Considering the subcellular location, potential mechanism of ceRNA network was predicted that OTUD6B-AS1 may compete with mir-144 to regulate or modify NUDCD1 and MARCH7 through miRNA sponge. OTUD6B-AS1 encodes the protein of ovarian tumor domain deubiquitinase 6B, while MARCH7 contributes to a RING domain of membrane bound E3 ubiquitin ligases. GO, KEGG and GSEA pathway analyses focused on ubiquitin-protein transferase activity, polyubiquitination, mTOR, Hippo and NOTCH pathways. Protein-protein interaction identified hub genes in ferroptotic regulation such as NEDD8 and HERC2, which were coding genes of ubiquitin ligase E3 as well. Hence, the balance of ubiquitination and deubiquitination induced by the interplay of ceRNA network could be pivotal process in ferroptosis modulation in LUAD. Conclusions: In summary, we reveal potential mechanisms that OTUD6B-AS1 may compete with mir-144 to regulate the expression NUDCD1 and MARCH7 through miRNA sponge or modifying protein structures, modulating ferroptosis by balance of ubiquitination and deubiquitination. Ferroptosis may participate in the recruitment of immune system and portrait of tumor immune microenvironment.
MEDB-31. THE CLINICAL SIGNIFICANCE OF EXTENT OF RESECTION IN MEDULLOBLASTOMA
Authors: Claire Keeling, Simon Davies, Debbie Hicks, Steven Clifford
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) patients determined to have a sub-total resection (STR), defined by &amp;gt;1.5cm2 post-surgical tumour residuum, receive intensified treatment regimes, but recently the designation of STR as a high risk feature is being questioned. We aimed to assess the clinical correlates of extent of resection (EOR) and its impact on survival, with particular consideration of EOR in relation to the four MB consensus molecular subgroups (WNT, SHH, Group 3, Group 4). We collected data from 1113 patients (n=419, UK CCLG institutions; n=694, published data) representing the largest ever combined cohort constructed to assess the impact of EOR in medulloblastoma. We performed association analyses and univariate/multivariate survival analysis using Kaplan-Meier, log-rank and Cox proportional hazard modelling, analysing overall survival (OS) cohort-wide and with reference to molecular subgroups and clinical features. Association analysis of the combined cohort evidenced that infant patients were more likely to have STR (p=0.02). In this whole-cohort analysis, EOR was significantly associated with survival in univariate analysis (HR 1.64, 95% CI 1.30-2.07, p=&amp;lt;0.001) but not in multivariate analysis. STR was variably prognostic in sub-cohort analyses of specific demographics and molecular subgroup; worse outcomes were observed in patients &amp;lt;5 years in SHH (p=0.044) and Group 4 (p=0.044). This was true for WNT patients &amp;gt;5 years old at diagnosis (p=0.034) although numbers were small and require validation in even larger cohorts. In this cohort of &amp;gt;1100 MBs, STR was significantly associated with a lower OS in univariate analysis, but this was driven by specific disease contexts (SHH and Group 4 patients &amp;lt;5 years old). STR was not independently prognostic overall or in any setting. We recommended that surgeons should continue to pursue maximal safe resection for all MB patients but suggest that consideration of STR as a high-risk feature should be disease context specific.